The present invention generally relates to devices and methods to treat an eye of a patient, and more specifically to intraocular implants that provide extended release of a therapeutic agent to an eye in which the implant is placed, and to methods of making and using such implants, for example, to treat ocular neuropathies.
Glaucoma is a progressive optic neuropathy characterized by excavation of the optic nerve head and visual field loss in the mid-periphery. Retinal ganglion cell death and consequent axon loss on the retinal nerve fiber layer result in cupping of the optic disc and visual field defects typical for glaucoma.
A major risk factor in glaucoma is thought to be elevation of the intraocular pressure (IOP) beyond the statistical norm, i.e. 21 mm Hg. The high IOP originates from an increased resistance to drainage of aqueous humor through the trabecular meshwork.
Although different forms of glaucoma are known, the most common form is adult onset open chamber angle glaucoma (OAG), which is age related and characterized by an open angle, IOPs over 21 mm Hg, a visual field defect typical for glaucoma, and a pathologically excavated optic disc.
Beta adrenergic receptor antagonists, also known as beta-blockers, are a mainstay and a first therapy choice for glaucoma.
The available beta-blockers are typically categorized as being either nonselective (also referred to as “nonspecific”), inhibiting both β1 and β2-adrenoceptors, or β1 selective, which means that β1-adrenoceptors are preferably inhibited.
Timolol maleate, (−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazo-3-yl)oxy]-2-propanol maleate, (1:1) salt, is a non-selective beta-adrenergic (beta1, and beta2) receptor blocking agent that does not have sympathomimetic or myocardial depressant activity. Timolol maleate, when applied topically, is effective in reducing elevated intraocular pressure in most forms of glaucoma, including acute angle-closure and secondary glaucomas.
Timolol maleate has been used clinically to lower intraocular pressure for treatment of chronic OAG for approximately 30 years. It does it by inhibiting aqueous humor production, and not by increasing outflow facility. However, as with many types of eye drops, it is believed that only about one percent of the daily regiment of either one drop (Timoptic XE® 0.5% q.d., Merck and Co., Inc., Whitehouse Station, N.J.) or two drops (Timoptic® 0.5% b.i.d. Merck and Co., Inc., Whitehouse Station, N.J.) actually gets absorbed inside the eyes to provide the therapeutic level. Research studies have shown that the bioavailability of timolol maleate can be improved by increasing its residence time in the precorneal area by adding a thickening agent to the drop formulation which tends to enhance the therapeutic effect of the drops.
The following patents and additional publications include disclosure which is relevant to and/or helpful in understanding the present invention: U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493. David L. Epstein, Chandler and Grant's Glaucoma, Lea & Febiger, (1986) pp 129-181; Physician's Desk Reference for Ophthalmic Medicines, 30 Edition, (2002) p 285; Chiao-His Chiang, Jing-Ing Ho, and Jiin-Long Chen, Journal of Ocular Pharmacology and Therapeutics, Volume 12, Number 4, 471, (1996). Calbert I. Phillips, R. Shayle Bartholomew, Anthony M. Levy, Jeffrey Grove, and Roger Vegel, British Journal of Ophthalmology, Volume 69, 217, (1985). The entire disclosure of each of these documents is incorporated herein by this reference.
There is still a need for more effective formulations and techniques for administering therapeutic agents, for example, beta adengergic receptor antagonists, for example, timolol maleate, to an eye in order to enhance bioavailability of the therapeutic agent to the eye.
It would be advantageous to provide eye implantable drug delivery systems, such as intraocular implants, and methods of using such systems, that are capable of releasing a therapeutic agent at a sustained or controlled rate for extended periods of time and in amounts with few or no negative side effects.